Acute kidney injury (previously known as acute renal failure) has a high morbidity and mortality. After developing a novel model of sepsis-induced AKI that employs cecal ligation puncture in elderly mice treated with fluids and antibiotics, we are using the model to study the pathophysiology of injury, to screen drugs, and to study their mechanisms of action, including conscious blood pressure by telemetry. We adjusted our mouse model by using outbred mice, which develop AKI at a younger age, and we established another model using comorbidity, namely pre-existing renal dysfunction, which is thought to increase susceptibility to AKI in patients. This acute-on-chronic syndrome has not been studied in animals, and the nephrology field is trying to gain more information about how this is manifest in patients. Because the model we used for pre-existing renal dysfunction is reversible, unlike the progression seen in CKD patients, we started with a partial renal ablation (5/6 nephrectomy) procedure, a classic rat CKD model, then adapted it to the mouse. We have characterized our model, and it has several hallmarks of progressive CKD, including hypertension, proteinuria, glomerulosclerosis, interstitial renal tubular fibrosis, anemia, and cardiac fibrosis. In order to make our CKD mouse model compatible with our sepsis AKI models, we tested three mouse strains, which had differential susceptibility to CKD. In the most susceptible strain, all aspects of CKD could be lowered by an angiotensin receptor blocker (olmesartan). Conversely, angiotensin II could convert a resistant strain to a susceptible strain. However, this effect is largely independent of blood pressure. 1) We combined our new mouse model for progressive CKD and our mouse sepsis-AKI model to study the 'acute-on-chronic'syndrome. We found that all indices of sepsis severity, including AKI, were increased by CKD. One common feature of sepsis is apoptosis of spleen cells. Surprisingly, we found that in the absence of sepsis, CKD increased spleen apoptosis, and this corresponded with the severity of CKD. This is the first demonstration of CKD-induced spleen apoptosis. CKD enhanced sepsis-induced increases in cytokines, including VEGF and HMGB1. Soluble-FLT1, a VEGF-binding peptide, decreased the severity of sepsis, but was ineffective in treating acute-on-chronic mice. Conversely, at a dose that anti-HMGB1 neutralizing antibody was ineffective in treating septic mice, anti-HMGB1 improved sepsis severity in acute-on-chronic mice. Splenectomy transiently decreased circulating HMGB1 levels, and during the trough anti-HMGB1 neutralizing antibodies were no longer effective in treating acute-on-chronic mice, which supports the spleen as one potential source of HMGB1. Despite baseline hypertension that was exacerbated by CKD, the CD-1 mice subjected to sepsis became hypotensive more rapidly than control mice subjected to sepsis. We continue to explore potential mechanisms and treatments for sepsis-AKI, CKD, and acute-on-chronic kidney disease.